Yoga vs Cognitive Processing Therapy for Military Sexual Trauma–Related Posttraumatic Stress Disorder

Key Points Question What is the effectiveness of Trauma Center Trauma-Sensitive Yoga (TCTSY) compared with first-line cognitive processing therapy (CPT) for posttraumatic stress disorder (PTSD) related to military sexual trauma in women veterans? Findings In this randomized clinical trial of 131 women veterans with PTSD who use US Department of Veterans Affairs health care, TCTSY had large within-group effect sizes, equivalent effectiveness to CPT, and a 42.6% higher treatment completion rate than CPT. Meaning The findings demonstrate that TCTSY is a cost-effective means to expand Veterans Affairs PTSD treatment options; increase access to acceptable, patient-driven, and effective PTSD treatment for women veterans; and provide a treatment option that could improve associated symptoms (eg, depression, anxiety).

Evidence indicates that yoga reduces stress and pain, and enhances sleep and functioning in civilian populations 4 .Results from pilot investigations demonstrate that yoga is beneficial in reducing PTSD symptoms in survivors of natural disasters 5 , as well as those with chronic PTSD 6,7 and combat-related PTSD 8 .A small number of studies indicate that yoga interventions are feasible and acceptable to U.S. Veterans 8,9 .Overall, the science of yoga is in early development, and studies examining the beneficial effects of yoga have been limited by methodological problems including small sample sizes, inadequate power, lack of randomization, and inconsistency among the yoga methods tested.In addition, these studies employed divergent measures to evaluate the effects of yoga with a lack of objective measurement of outcomes including biological or psychophysiological markers that are associated with previous psychological trauma and with PTSD symptoms.These include inflammatory markers, exaggerated acoustic startle response to darkness (termed darkenhanced startle), and depressed heart rate variability [10][11][12][13] .In addition, studies that recruit Veterans with PTSD often disproportionately under-represent or do not include data specific to women; furthermore, sexual trauma is typically not considered, although it is the most common cause of PTSD among women Veterans.
In 2014, our team conducted a one-year NRI pilot study (n=42), referred to as Project Stress-Less, which was the precursor to the current NRI study.In Project Stress-Less, a trauma-sensitive Hatha yoga intervention was conducted in parallel to a Cognitive Processing Therapy-Cognitive group (CPT-C) in a sample of women Veterans with PTSD related to MST.Hatha yoga is a gentle, slow approach to physical postures and includes breath work and mindfulness.The specific aims of Project Stress-Less were to: assess the feasibility of recruitment and retention (including randomization and intervention acceptability) in yoga versus evidence-based group psychotherapy; to evaluate study participants' adherence and yoga teachers' fidelity to the yoga intervention; and to assess the feasibility of obtaining biological and psychophysiological data for a study of yoga as a treatment for PTSD in this population.We succeeded in achieving these aims.In addition, our results support our hypothesis for the proposed study that this Trauma Center-Trauma Sensitive Yoga intervention may be effective in reducing PTSD symptoms, chronic pain, insomnia, and biological and psychophysiological hyper-responsivity.The proposed RCT is the culmination of the successful implementation and feasibility demonstrated throughout the one-year Project Stress-Less pilot study.

The specific aims and hypotheses of the proposed RCT: Aim 1:
To evaluate the effectiveness of Trauma Center-Trauma Sensitive Yoga (TC-TSY) compared to Cognitive Processing Therapy (CPT) in reducing PTSD symptoms, chronic pain, and insomnia in women Veterans with PTSD related to MST.

Hypothesis 1:
Participants in the TC-TSY group will show statistically and clinically meaningful reductions in PTSD symptoms, chronic pain and insomnia (PTSD Checklist-5 (PCL-5) scores, Clinician Administered PTSD Scale (CAPS-5) scores, Brief Pain Inventory (BPI) scores, Pittsburgh Sleep Quality Index (PSQI) scores compared to CPT-C group results following treatment.

Aim 2:
To evaluate the effectiveness of TC-TSY as compared to CPT in improving quality of life and social functioning in women Veterans with PTSD related to MST.

Hypothesis 2:
Participants in the TC-TSY group will show statistically and clinically meaningful improvements in quality of life and social functioning (VR-12, PROMIS measures) compared to CPT group results.

Aim 3:
To evaluate the effectiveness of TC-TSY as compared to CPT on biological stress response and psychophysiological hyperresponsivity.

Hypothesis 3:
Participants in the TC-TSY group will show statistically and clinically meaningful changes in biological stress response (inflammatory cytokines (IL-6, IL-10), C-reactive protein levels) and psychophysiological hyper-responsivity (dark-enhanced startle measures and heart rate variability) health problems including PTSD, depression, anxiety, chronic pain, sleep disturbances, wide-ranging physical symptoms, substance abuse, and negative health behaviors 3 .For example, compared to women with no prior history of sexual assault, women Veterans who experienced MST had a nine-fold risk for PTSD 28 .PTSD is a strong predictor of suicidal ideation and suicide attempts for both men and women 29 .In 2009 and 2010, PTSD was the top diagnosis for women Veterans treated by the VA 30 .These multiple symptoms and health problems may be compounded in this population due to high rates of additional trauma (e.g., combat trauma, intimate partner violence, and/or child abuse) 16 .The multiple health problems for which this population is at increased risk can result in significant health problems, disability, decreased quality of life and impaired social functioning 19, 31, 32 .
Chronic pain is a persistent problem for women Veterans.Dobie and colleagues 32 reported that, in their study of nearly 2000 female Veterans, those with PTSD were more than twice as likely to report bodily pain in the previous month.Co-morbidity between PTSD and pain is as high as 80% in the general and Veteran populations 33,34 .Chronic pain and insomnia are common problems in female survivors of multiple trauma exposures, particularly interpersonal violence and childhood trauma 16, 35- 37 .The interplay between PTSD symptoms, chronic pain, and insomnia creates a symptom cluster in which individual symptoms cause or exacerbate other symptoms synergistically 38 .Of the four diagnostic PTSD symptom clusters (re-experiencing, avoidance, negative cognitions and mood, and arousal), hyperarousal symptoms may account for more reported health problems in women Veterans than do re-experiencing and numbing symptom clusters 39 .Logically, an intervention that targets multiple symptoms within this broader symptom cluster (PTSD symptoms, chronic pain, and insomnia) is most likely to be effective.

Scientific Rationale Trauma and Women Veterans.
Women Veterans often have high rates of pre-military, military, and post-military trauma.In an integrated literature review, Zinzow (2007) and colleagues found that more than 80% of women Veterans reported at least one type of trauma and had higher rates of trauma than their civilian counterparts 3 .In a study we conducted in the Atlanta VA Medical Center, we found that of 135 participants, 95.4% reported at least one trauma in addition to MST, most notably sexual abuse as adult civilians (77.0%) and as children (52.6%).Nearly one in four reported experiencing all three types of childhood abuse: emotional, physical and sexual 16 .Given the high rates of cumulative trauma in addition to MST among women Veterans, particularly those with PTSD, it is not feasible to isolate the effects of MST on autonomic nervous system responses, for example the hyperarousal associated with PTSD.The rationale behind our focus on MST in this study is related to a PTSD intervention specific to women who experienced MST.Although the focus of our study is MST, we hope that our findings may increase overall understanding of the immunological and neurobiological factors associated with trauma exposure.In this study, we will investigate autonomic nervous system and inflammatory responses associated with PTSD.Detailed descriptions of these immunological and psychophysiological responses and how they relate to trauma, pain, and sleep are provided below.This will establish the foundation of the theoretical framework for this study, that is, the postulated counter-acting effect of yoga on harmful inflammatory and psychophysiological manifestations of psychological trauma and PTSD.

Psychophysiology of PTSD
Understanding the neurobiology of PTSD is central to understanding the potential impact of yoga on PTSD and its associated symptoms of chronic pain and insomnia.PTSD is associated with altered neurobiological responses, including autonomic nervous system dysfunction, notably increased sympathetic nervous system activity and decreased parasympathetic nervous system activity.Under most circumstances, the sympathetic nervous system functions in opposition to the parasympathetic nervous system.Early and/or repeated exposure to extreme stress or trauma affects an individual's long-term capacity to modulate the sympathetic nervous system and parasympathetic nervous system responses to subsequent stress.Activation of the sympathetic nervous system is traditionally associated with the "fight or flight" response to an extreme trauma, which is characterized by increased heart rate, increased cardiac output, and increased blood pressure.While activation of the parasympathetic nervous system is characterized by reduced heart rate, reduced cardiac output, and reduced blood pressure.Inadequate parasympathetic nervous system response tips the sympathetic nervous system/parasympathetic nervous system balance towards hyperarousal, difficulty in responding to stressors, and an impaired relaxation response, all of which are characteristic in posttraumatic stress responses.Heightened sympathetic nervous system activity is marked by an increased basal heart rate, a robust cardiovascular marker of PTSD.

Inflammatory Processes, Trauma, Pain, and Sleep
PTSD and chronic pain are also associated with immunologic responses, including inflammatory processes such as the inflammatory cytokine cascade.Inflammatory cytokines and C-reactive protein have been associated in various studies with trauma exposure, subsequent PTSD, and chronic pain.There is a relationship between sleep and the immune response; however the association of cytokines with sleep disturbances is inconclusive.Given these relationships, cytokines and C-reactive protein may be key biomarkers of the effect of yoga on PTSD symptoms, chronic pain, and insomnia.

Inflammatory Cytokines, C-Reactive Protein, Trauma Exposure, and PTSD
As with other physiological systems, the sympathetic nervous system and parasympathetic nervous system have opposite effects on inflammation and the immune response.Sympathetic nervous system stimulation of white blood cells, via the release of the neurotransmitter norepinephrine and its subsequent binding to alpha-adrenergic receptors, increases pro-inflammatory cytokine release from macrophages, neutrophils, and T cells 40 .In stark contrast, parasympathetic nervous system stimulation of surrounding macrophages and other white blood cells, via the release of the neurotransmitter acetylcholine, inhibits pro-inflammatory cytokine release 40 .Elevated levels of inflammatory markers have been found in survivors of trauma (interleukin-6 (IL-6)) and individuals with PTSD (C-reactive protein; interleukin-1 (IL-1); IL-6, IL-10) 41,42 .Alterations in C-reactive protein and cytokine activity are also associated with symptoms that commonly co-occur with PTSD, including depressive symptoms, fatigue, chronic tissue inflammation, and enhanced sensitivity to pain 43 .Elevated inflammatory markers are also associated with "sickness behavior," an inflammation-related syndrome characterized by depression, fatigue, reduced physical activity, changes in sleep and appetite, and an increased responsiveness to pain 44 .

Inflammatory Cytokines and Pain Response
The relationship between inflammatory markers and pain suggests that these biomarkers may also be useful in understanding the mechanism by which chronic pain may be maintained in patients with PTSD.Elevations in pro-inflammatory cytokines (IL-1β, IL-2, IL-6, TNF-α) and C-reactive protein have been shown to correlate with increasing pain intensity in patients with chronic pain 43 , psychological stress 45 and PTSD 46 .The mechanisms by which inflammatory cytokines are believed to cause hyperalgesia are attributed to neuroplastic changes within the peripheral and central nervous system, which alter nociceptive signaling, and as such, can increase sensitivity 47 .IL-6 has been shown to act as a messenger relaying chemotactic peripheral immune signals to the central nervous system 43 .Similarly, glial cells within the brain secrete cytokines, further altering peripheral nociceptive responses affecting the subjective experience of pain 43 .This complex interplay is hypothesized to contribute not only to pain, but also to fatigue and depressive symptomatology 48 .

Inflammatory Cytokines, C-Reactive Protein, and Sleep Impairment
There is a bidirectional relationship between sleep and the immune response.C-reactive protein and cytokines, including TNF, IL-1, IL-4, IL-6, and IL-10, have been established as part of the biochemical sleep regulatory process 49 .In addition to changes in C-reactive protein and cytokine activity 49,50 , disordered sleep is associated with changes in stress hormone levels and reduced heart rate variability, indicative of greater sympathetic nervous system activity 51 .Because the associations between sleep and cytokines remains inconclusive and because it is unclear how cytokine levels relate to subjective and objective indices of sleep quality, further investigation of the role of cytokines in sleep in women with PTSD is needed.Pain disrupts sleep, with a majority of patients with chronic pain (50% to 70%) reporting poor sleep quality 52 .Because pain and disrupted sleep often co-exist, it is difficult to determine whether poor sleep or pain is triggering changes in immune function.Taken together, these data on the relationships between inflammatory markers, chronic pain, and sleep disturbances suggest that C-reactive protein and certain cytokines may be key biomarkers of the effects of yoga on symptoms of PTSD and associated insomnia and chronic pain.

Effectiveness of Yoga for Depression, Anxiety, Insomnia, and Physical Pain
Yoga is increasingly being studied as a therapeutic intervention for a variety of physical and mental health problems and symptoms 53 .Growing evidence demonstrates that yoga is safe and effective in treating depression and anxiety 54,55 , and improving sleep quality 56 and insomnia in post-menopausal women 57 .Yoga has also been found to significantly reduce general musculoskeletal pain and disability 58,59 .The majority of researchers investigating yoga as a treatment for pain have focused on chronic low back pain.Groessl et al. studied yoga for chronic low back pain in male and female Veterans and found that while both women and men had significant reduction in pain and depressive symptoms with increased energy and mental health-related quality of life, women had significantly larger benefits than men 60 .PTSD symptoms were not evaluated in this study, yet 30% of the men and 15% of the women in the sample reported having a PTSD diagnosis.

Yoga in the Treatment of Trauma-Exposed Individuals
Yoga has been shown to reduce anxiety and depression in male and female active duty military personnel, as well as male and female Veterans with PTSD 9,61,62 .Trauma Center-Trauma Sensitive Yoga, the modality to be used for the current study, was developed specifically for civilian women survivors of childhood sexual trauma with PTSD 6,63 .Trauma Center-Trauma Sensitive Yoga focuses on interoception (i.e., the sense of the physiological condition of the body) and links breath with movement, builds body awareness and self-regulation, and uses invitational rather than instructional or commanding language.Emerson, a member of our research team, and colleagues (2014) found that Trauma Center-Trauma Sensitive Yoga decreased symptoms of PTSD in a study of civilian women (n=60) with chronic PTSD 7 .We have evaluated Trauma Center-Trauma Sensitive Yoga with a different and under-studied population, women Veterans with PTSD who experienced MST and reported chronic pain and insomnia, in two preliminary projects preceding the development of this RCT.
Within the few studies of yoga as a potential intervention for PTSD, most researchers have relied on self-report data.In Project Stress-Less, we established the feasibility of using objective outcome measures such as inflammatory biomarkers (cytokines and C-reactive protein) and psychophysiological markers, including the acoustic startle response and heart rate variability.Emerging research findings strongly suggest that yoga is an effective therapeutic intervention for the symptoms to be evaluated in this study.
However, the body of research examining the beneficial effects of yoga is limited by methodological problems including inadequate power, lack of randomization, and inconsistency among the yoga procedures and measures used to assess yoga effects 25,26 .In addition, studies that recruit Veterans with PTSD often disproportionately underrepresent or do not include data specific to women; furthermore, sexual trauma is typically not considered, although it is the most common cause of PTSD among women Veterans.

Heart Rate Variability (HRV)
Evaluation of parasympathetic nervous system and sympathetic nervous system activity is typically accomplished via measurement of HRV.HRV reflects the central nervous system's ability to respond immediately to fluctuations in blood pressure occurring with each beat; high-frequency heart rate variability indicates fine control via a parasympathetic nervous system-dominant response while low-frequency heart rate variability reflects both sympathetic nervous system and parasympathetic nervous system activity.HRV is measured via electrocardiographic monitoring of the R-R interval.Computerized power spectral analysis is used to identify low-frequency versus the high-frequency components of HRV, reflecting sympathetic nervous system and parasympathetic nervous system activity.Decreased HRV has been correlated with morbidity and mortality from diverse diseases, including anxiety and depression 64 and cardiovascular disease 65 .The relationship of decreased HRV to morbidity and mortality in these disorders is believed to be related to the inverse relationship between HRV and inflammatory markers: that is, the lower the HRV, the higher the level of inflammatory markers.Heart rate variability has been empirically studied in patients with PTSD; most researchers report decreased high-frequency heart rate variability during rest 66 .Heart rate variability measures demonstrate gender differences; a recent study found that increased heart-rate response to trauma reminders soon after trauma exposure predicted PTSD diagnosis six months later in women but not men 67 .Lower heart rate variability has recently been found to correlate with MST in women Veterans with PTSD 68 .The proposed study will measure heart rate variability as a psychophysiological marker to assess intervention outcomes.

Dark Enhanced Startle
Dark-enhanced startle is an ecologically valid psychophysiological paradigm for assessing contextual levels of fear and anxiety.We have previously shown the magnitude of the acoustic startle (blink) response is exaggerated in previously traumatized women when assessed in darkness versus light conditions 69 .Using startle measures, studies have shown that patients with PTSD show overgeneralization of fear and an inability to inhibit fear responses in the presence of safety 70 .Impaired fear inhibition may be a specific biomarker of PTSD 70 , specifically autonomic hyperarousal.In humans, the startle response is increased in darkness as compared to well-lit environments, a phenomenon termed darkenhanced startle.Dark-enhanced startle is a laboratory analogue of sustained anxiety and represents a clinically useful tool for assessing anxiety-like behaviors and hyperarousal as they relate to symptom severity.

Psychophysiological Markers Associated with Pain Response
Vascular parameters, including heart rate and blood pressure, skin conductance measures and electromyographic readings, are the most commonly used physiological markers of patients' subjective experiences of chronic pain syndromes.However, these measures may be differentially influenced if the pain syndrome stems from sympathetic nervous system hyperarousal (complex pain syndromes), musculoskeletal (back pain) or vascular origins (migraine headache), as well as the individual's psychological coping abilities.Experimental studies in healthy men demonstrate that increasing levels of pain are associated with increases in heart rate 71 ; however, this association has not been found in women.Changes in heart rate variability may be a better measure of reduced hyperarousal and pain in women than heart rate, although the relationship between heart rate variability and pain in women is complex and may vary based on whether the pain is acute or chronic.The proposed study will add a better understanding of the relationship between heart rate variability and pain in women, specifically in those with PTSD.

Theoretical Framework
The proposed study is based on a theoretical framework in which the impact of the yoga intervention is conceived to directly counteract immunological and psychophysiological responses to trauma.Our proposed model suggests that, through its effects on the central nervous system, yoga reduces the inflammation and psychophysiological hyperarousal associated with trauma and improves autonomic regulation.We propose that these effects (reduced inflammation and hyperarousal and improved autonomic regulation) are one pathway through which the practice of yoga may lead to reduced PTSD symptoms, chronic pain and insomnia.Because of the data suggesting a bidirectional relationship between inflammation/autonomic dysregulation/hyperarousal and PTSD symptoms/chronic pain/insomnia, it is also expected that the yoga intervention will facilitate improved functioning in both domains (inflammation/autonomic dysregulation/hyperarousal and PTSD symptoms/chronic pain/insomnia).It is hoped that this synergistic improvement across the two domains will counteract the alternate process in which increases in one domain lead to increases in the second, thereby increasing the overall negative impact of trauma exposure.
In other words, our theory proposes that the practice of yoga produces a relaxation response that counteracts the physiological stress associated with PTSD and other associated trauma-related chronic health problems 56 .As described above, the beneficial effects of yoga on stress are postulated to result from control of physiologic reactivity, decreased sympathetic activity and activation of the parasympathetic nervous system 4,72 , since yoga is associated with increased heart rate variability 72,73 .Slow and rhythmic yoga breathing techniques have been found to synchronize sympathetic nervous system and parasympathetic nervous system vagal activity outflow, resulting in increased heart rate variability and arterial baroreceptor sensitivity characterized by a sense of calm 74,75 .The evidence that yoga increases the ability to focus attention, calm the mind and relax the body 4,72 , resulting in reduced respiratory rates 74 and increased cardiac vagal modulation and heart rate variability 72,73 , suggests that yoga may reduce the acoustic startle response by decreasing hyperarousal, a finding supported in Project Stress-Less.Additionally, preliminary research demonstrates that yoga is associated with reduced C-reactive protein and inflammatory cytokines, specifically IL-6 76 .
This RCT will investigate a novel approach to treating not only PTSD symptoms, but chronic pain and insomnia, which appear to be the most intractable symptoms associated with MST and PTSD 19 .Our theoretical framework suggests that yoga will reduce PTSD symptoms, chronic pain, and insomnia via psychophysiological mechanisms, rather than the cognitive mechanisms of current psychotherapeutic treatments.Further, the antiinflammatory mechanism of yoga may minimize inflammatory sequelae of MST and PTSD, thereby reducing conditions with which PTSD is co-morbid and, in turn, improving general health.Preliminary Data Trauma Exposure and Mental and Physical Health Symptoms in Women Veterans with MST and PTSD In a study of women in a VA Women's Trauma Program (n=200), Kelly (PI) et al found that the women's PTSD symptoms were highly correlated with major depression (r=.715; p<.001), sleep difficulty (r=.484; p<.001), pain (r=.249; p<.01), and lower quality of life (r=.469;p<.001) 16 .In a random sample (n=50) of our Women's Trauma Program patients, 80% had chronic pain, e.g.low back pain (40%) and headaches (48%), unrelated to malignancy, injury or surgery in the previous three months.These data demonstrate the substantial co-morbid mental and physical health problems of women Veterans with PTSD and MST in our setting.PTSD Treatment Seeking by Women Veterans who Experienced MST The PI and several co-investigators on the proposed study conducted a qualitative study to explore the barriers and facilitators to PTSD treatment seeking by the target population 79 .Participants were recruited from the Women's Trauma Program after completing the intake process.A constructivist grounded theory approach, was used to collect data via individual semistructured interviews and to conduct data analysis.These patients (n=12) had clinically severe symptoms of PTSD (PCL = 59.62; clinically significant symptoms are defined as ≥ 50 in Veteran populations), major depression (BDI-II mean 33.18; severe symptoms are defined as ≥ 29), and somatic complaints (PHQ-15 mean 30.10; severe symptoms are defined ≥ 15).Several of the women in this study described physical pain, difficulty sleeping, perceived poor physical health, multiple diagnosed medical problems, and significant weight gain as reasons for seeking PTSD treatment.

Project Stress-Less (NRI 12-417): Trauma Center-Trauma Sensitive Yoga for
Women Veterans with PTSD symptoms and MST exposure.In the Project Stress-Less pilot study, we enrolled 42 women Veterans with PTSD related to MST who were seeking mental health treatment for PTSD in the Atlanta VAMC Women's Trauma Program and who reported chronic pain.Participants were randomly assigned to the two study conditions: Trauma Center-Trauma Sensitive Yoga or Cognitive Processing Therapy-Cognitive (CPT-C) groups.These groups did not differ significantly on age, race, or education, however the CPT-C group had higher clinician assessed PTSD severity (CAPS), depressive symptoms (BDI-II), and pain (POQ) at baseline.Of note, participants were notified of their group assignment prior to data collection.Several participants who were randomly assigned to the CPT-C group expressed dismay at their assignment.One possible explanation of the higher symptom severity in this group at baseline is that some in CPT-C were disappointed in their randomization assignment.To address this possibility, in the proposed RCT, we will collect baseline data before randomization.
The TC-TSY protocol 7 involved ten weekly 90-minute group sessions.The standard CPT-C protocol was used and included twelve weekly 90-minute group sessions.We conducted two cohorts of the interventions concurrently and collected data at four time points: Baseline (T1), mid-intervention (T2), two-weeks post-intervention (T3) and three months post-intervention (T4).
The specific aims of Project Stress-Less were to assess the feasibility of recruitment, retention, intervention implementation and obtaining biological and psycho-physiological data.In addition, we looked at these measures to determine their use as outcome measures for yoga and PTSD research in this population.These aims were achieved.All data have been analyzed and are supportive of our hypotheses on the mental and physical benefits of the trauma sensitive yoga intervention.An outline of feasibility and intervention results is provided below.

Study Recruitment and Retention Feasibility
Retention of participants in the TC-TSY group was higher at each time point than in the CPT-C group.Of note, some individuals declined to participate or withdrew from the study without a guarantee of receiving the yoga intervention or when randomized to the CPT-C arm of the study.In the current RCT, potential participants will be informed that they can receive the intervention they are not assigned to after completion of their participation in the study at no cost.
We based our overall study attrition estimate on that of van der Kolk and colleagues 77 .However, our population and setting was different in several ways: 1) our sample had higher levels of complex trauma (Table 3); 2) our sample was less educated and had higher rates of unemployment; and 3) our setting in a VA Medical Center versus a private clinic was undesirable to participants, was not easily accessible by participants, and had limited parking.We are conservatively accounting for 50% retention in the current RCT, but hope to achieve higher retention with the implementation of several changes to the setting, protocol and retention strategies.

Intervention Feasibility: Completion Rates and Acceptability to Participants
We determined the number of intervention sessions and defined intervention completion based on published standards for the specific interventions.The TC-TSY intervention is a manualized curriculum of ten weekly sessions.Emerson and colleagues, who designed the intervention, defined intervention completion as attendance at seven of the ten sessions 7 .For the CPT-C group, treatment completion was defined as attendance at nine or more of the twelve sessions, based on the definition used in most empirical studies.However, it is important to note that in the Women's Trauma Program, drop-out rates for CPT-C groups average 50%.The retention rate in the TC-TSY groups (58.8%) was significantly higher than in the CPT-C groups (36%).The higher retention rates for the TC-TSY group could suggest that the yoga sessions may be a more acceptable form of treatment for the target population.
Qualitative data were collected via focus groups and individual interviews after the first session, mid-intervention and at post-intervention data collection points.Participants were receptive and engaged in TC-TSY sessions.Positive feedback given about TC-TSY was that participants found the intervention to be calming and helpful for stress reduction.Several also reported an increased awareness of their bodies as a result of yoga.Some participants in the CPT-C group stated that they appreciated the process of learning how to challenge their thoughts, though many found the process difficult.Most participants in both groups found getting to the sessions difficult due to traffic and parking.Participants also shared that they would prefer to have the group sessions somewhere other than the VA, as this location served as a trigger for PTSD symptoms.Most recently, the Women's Trauma Program has moved from the main VA Medical Center to a community based outpatient clinic in a more accessible location, with ample parking, and a quieter environment.We anticipate that this new location may address the concerns voiced by previous participants in Project Stress-Less.

Intervention Fidelity
Group sessions were led by two yoga teachers experienced in teaching Trauma Center-Trauma Sensitive Yoga and who received 20 hours of in-person training and 20 hours of consultation calls from David Emerson, a collaborator on the pilot study and the current project.The teachers co-taught the sessions, allowing for peer monitoring and feedback.The teachers completed summary and debriefing sheets after each session and had consultation calls to review each session.Intervention fidelity was maintained and no deviations were identified.We will adhere to the same plan to maintain fidelity on the current study.

Data Collection & Participant Burden
Study visits typically lasted 3-5 hours and involved some unnecessary participant burden.Based on feasibility data and participant feedback, data collection has been streamlined for the current study.Moving forward, we have opted to remove sleep actigraphy and several interview/self-report measures which lacked clinical utility or were redundant.In addition, we will not collect dark-enhanced startle/heart rate variability data and inflammatory markers at mid-point (Time-2 Visit), primarily to decrease participant burden.

Feasibility of Measuring Immunologic and Psychophysiological Biomarkers as Outcomes
In Project Stress-Less, participants' willingness and tolerance of blood collection and darkenhanced startle/heart rate variability assessments were greater than anticipated.We had hypothesized that the hyperarousal associated with PTSD might pose potential technical and data interpretation challenges, however very few participants declined or discontinued these procedures.We have established stream-lined data collection processes, and the technical difficulties we encountered with dark-enhanced startle/heart rate variability data collection have been resolved with the purchase of new equipment and more experienced staff.

Preliminary Effectiveness Results
Though not an aim of the pilot study, we analyzed available data to explore the effectiveness of TC-TSY compared to CPT-C.These analyses suggest, descriptively, that the TC-TSY group experienced improvements in PTSD severity, depression, pain levels, and acoustic startle response, from baseline to two-week post intervention.The TC-TSY group had: 1) a reduction in self-reported PTSD symptoms; 2) a reduction in clinician assessed PTSD (CAPS); 3) substantial decreases in pain 4) distinct decreases in depressive symptoms.The TC-TSY group showed notable decreases in acoustic startle response (dark-enhanced startle) while the CPT-C group's startle response increased.Data indicate that TC-TSY as compared to CPT-C may represent an effective means of reducing the fear-related sequelae of trauma exposure as evidenced by psychophysiological indices, i.e. dark-enhanced startle and heart rate variability.This will be further explored in the current RCT with enhanced recruitment and statistical power.

C. STUDY DESIGN AND METHODS COVID-19 Contingency Plan (Atlanta and Portland)
As a result of the COVID-19 pandemic, local directive (3/12/2020) suspended study intervention visits for this study and national (3/17/2020) directive suspended all nonessential, in-person visits until further notice.Thus, we have modified the study design and methods to conduct group interventions and data collection virtually when possible.All interview-based assessments will be conducted via a suitable/authorized remote conferencing service between participant and research coordinator, i.e.Zoom Pro.All group intervention sessions will be conducted via a suitable/authorized remote conferencing service with group facilitators and group participants, i.e.Zoom Pro.Participant self-report will be entered by participant via direct entry of fully de-identified data into a secure REDCap web-based application.In the event self-report and/or interview-based assessments cannot be conducted via remote/virtual methods, the assessments will be administered via telephone.Informed consent and HIPAA authorization will be emailed and mailed to potential participants and reviewed via remote conferencing service or telephone.Once signed consent has been received by research staff, data collection visits and interventions will be conducted in the aforementioned manner.We will suspend collection of in-person physiological data at the Atlanta site.Portland site will utilize mail and drop off/ pick up for data collection kits such as portable KardioScreen ECG machines finger-stick blood collection method, portable BodyGuard HRV devices (Atlanta and Portland).Devices will be cleaned/sterilized in concordance with manufacturer's instructions and CDC guidelines.

Setting and Location (Atlanta)
This is a multi-site study with Atlanta VA Health Care System as the Coordinating Center.Study procedures in Atlanta will be conducted at the VA Clinical Studies Center.The Acoustic Startle Lab and the Atlanta VA Trauma Recovery Program located at the Henderson Mill Annex will also be used for intervention and data collection visits.

Clinical Studies Center (CSC)
The CSC is a professional center designated to facilitate human subjects' research at the Atlanta VA Medical Center and includes a laboratory (equipped with centrifuge, freezer, and biosafety hood), phlebotomy services for participants, and exam rooms to conduct study visits.The study team will utilize these services throughout the study.

Acoustic Startle Lab
The Acoustic Startle Lab is conveniently located on the fifth floor of the main VA.This space is dedicated to the collection of psychophysiological data (acoustic startle, HRV, skin conductance) and includes a Biopac System, sound attenuating audiology booth and control room for staff.

Trauma Recovery Program
The Trauma Recovery Program is located on the fourth floor of a leased VA space in the Henderson Mill Annex (2296 Henderson Mill Road) and contains ample parking, office space and group rooms.Study procedures including informed consent, selfreport measures, interview-based assessments and dark psychophysiological data collection will also be conducted in a dedicated research office within the TRP.
Additionally, the yoga and CPT group sessions will be conducted in the TRP group rooms.

Setting and Location (Portland)
Study procedures will be conducted at the VA Portland Health Care System at both the Portland and Vancouver VA Medical Centers.Specifically, intervention sessions (Yoga and CPT) will be held at the VAPHCS Vancouver, WA campus and data collection visits will be conducted at the main VAPHCS campus in Portland, OR.Once IRB approval is received, space will be designated for data collection and intervention sessions for the duration of this study.

Participant Selection Inclusion Criteria
1) Women Veterans who experienced military sexual trauma; 2) Meets DSM-V criteria for PTSD due to military sexual trauma 3) Difficulty falling asleep or difficulty staying asleep (insomnia) 4) Ability to give informed consent; 5) Willing to participate in either TC-TSY or CPT; 6) Available to attend the study intervention at the scheduled times.Exclusion Criteria 1) Diagnosis of schizophrenia with significant psychotic symptoms (determined via clinician interview); 2) Current, active suicidal intent or plan (determined via clinician interview); 3) Current severe alcohol substance use disorder (determined via clinician interview); 4) Medical conditions that can contribute significantly to psychiatric symptoms, including poorly controlled hypo/hyperthyroidism, kidney or liver failure (determined via review of medical record); 5) Dementia (determined via review of medical record); 6) Moderate or severe traumatic brain injury (TBI) or other cognitive impairment sufficient to interfere with ability to give informed consent (determined via review of medical record); 7) Pain due to acute injury (<3 months), post-surgical pain (<3 months) or pain due to malignancy (determined through Veteran self-report and/or medical record); 8) Receiving mental health trauma focused therapy (TFT) treatment outside of the VA (determined through Veteran self-report); 9) Current engagement in trauma-focused treatment, yoga practice or other treatment/intervention at odds with the study intervention.

Recruitment (Atlanta)
Veterans will be recruited in the following ways: 1) Veterans may self-refer from flyers and brochures located in waiting areas and bulletin boards located in various clinics within the VA including the TRP, Women's Wellness and Primary Care.Flyers may also be distributed during VA sponsored events (For Example: Vet Fest, Heart Health events, VA Research Day).Following initial contact, a phone screen and chart review will be completed to assess eligibility.2) Clinicians within the TRP, Women's Wellness and Primary Care, and any other outpatient clinic or community-based out-patient clinic (CBOC) may also refer patients to the study.Veterans will be given the option to contact the study team directly or they may give consent to be contacted by a member of the study team.A brochure with an overview of study information and contact information may be provided to the interested Veteran by the clinician.Following initial contact, a phone screen and chart review will be completed to assess eligibility.3) Study staff will conduct ongoing chart review of patients who have been referred to TRP for services, and/or who have recently completed TRP intake.The study team will contact TRP clinicians regarding any patient who could be a potential candidate for the study.At that time, the TRP provider will discuss the study with the Veteran and if the Veteran expresses interest, TRP staff will provide study contact information or facilitate an introduction to the study team.The study team and TRP providers will work closely to make sure that anyone who is interested will be screened for the study.4) Study staff will attend TRP psychoeducational groups and staff meetings to present the study.Flyers with study contact information will be provided so that anyone who is interested may contact the team directly.5) Study staff will conduct pre-screening of selected out-patient clinics within the Atlanta VAHCS to identify potential participants, for example, Women's Wellness.We have obtained a partial HIPAA waiver for this purpose.The clinical providers of potentially eligible participants will be contacted to request that they inform the patient of the study.6) Recruitment will also be done outside of the VA setting.Study staff will place flyers in clinics, centers, college campuses, and other locations in the community which have the potential to reach women Veterans.Study staff will get consent from these locations prior to posting the flyers.In addition, study staff will attend community events geared towards Veterans in order to explain the research study to providers and provide information to those who may be interested.Note: The study team will not be recruiting non-Veterans into the study, but will expand recruitment efforts outside the VA setting.7) To supplement provider referrals, we may also conduct initial outreach to potentially eligible participants via recruitment letters, as required by the IRB.In addition to patients identified via pre-screening, we propose to use the VA Informatics and Computing Infrastructure (VINCI) databases to identify patients at the Atlanta VA Health Care System who may be eligible for participation in the research study.We will ask the VINCI data managers to pull requested data from the Corporate Data Warehouse (CDW).The data pulled from VINCI will include patient names, phone numbers and address, dates, social security number, visit and hospital information, and other health information.This information will be necessary to recruit participants, and a partial HIPAA authorization waiver has been obtained.These identified data will be directly transferred electronically from the VINCI environment to the secured research server VHAATGFPC10 located in the OIT server room at the facility.This will be done by Christine Jasien, Atlanta VAMC statistician.The servers are managed by the Atlanta and Region 3 OIT offices and security is managed by the Information Security Officers at that facility.The server room has appropriate security controls in place (including a locked room, password protection, and encryption), and the drive that the data will reside at will be controlled so that only the research team has access to the data.Patients identified for contact will be sent an IRB-approved letter referring to the study as "Project Stress-Less" for privacy purposes.The study team will discuss the study with interested patients by telephone, providing further information about the study.The PI has been granted a partial HIPAA waiver in order to conduct these prescreening/recruitment activities which facilitate identification of eligible participants.Recruitment rates will be calculated by comparing the total number of patients screened for the study to the number of patients who provide informed consent to participate.

Recruitment (Portland)
Veterans will be recruited in the following ways: 1) Veterans may self-refer from flyers and brochures located in waiting areas and bulletin boards located in various clinics within the VAPORHCS including the Mental Health Clinic (MHC), Women Veteran Health Clinic (WVHC), PTSD Clinical Team (PCT), and Primary Care Mental Health Integration (PCMHI).Following Veteran initiated contact, a phone screen and chart review will be completed to assess eligibility.2) Clinicians within participating mental health clinics and any other out-patient clinics (CBOC) may also refer patients to the study.Veterans that are identified by treatment providers (who have pre-existing relationships with the potential participant), meet criteria, and are interested in participation will be provided a verbal explanation and printed IRB-approved study flyer from that provider who also will collect verbal consent to be contacted by a study member.At that time, Veterans will be given take home information about the study purpose and details.Consent of potential participants to be contacted by a study team member will prompt the treatment provider to refer the Veteran by first and last name along with last 4 digits of the Veteran's SSN to the study team either via encrypted email, phone, or by attaching a study team member as a cosigner to a CPRS note.Providers will document in CPRS the conversation with the Veteran and the Veteran having consented to be contacted for study participation.Following Veteran consent to be contacted, a study team member will follow up with a phone screen and chart review will be completed to assess eligibility.3) Study staff will conduct pre-screening of selected out-patient clinics within the VAPORHCS to identify potential participants.In cases where a potential participant was not identified as such by other recruitment efforts described in this waiver (e.g. via their treating clinicians or flyers), under the principle of beneficence, the study should be made available to them.In those cases, a study team member will request permission from the clinician in charge of the clinic to reach out to the potential participant.If granted permission by the clinician in charge to contact the potential participant, a study team member will contact the potential participant.That contact will include a letter to the identified potential participant acknowledging PHI that assists the Veteran in understanding why they were identified for participation and will be signed by the treating clinician or clinician in charge.In addition, that contact will include a letter signed by a member of the study team introducing the study to the potential participant as a means for recruitment.This letter will not be individualized and will include a brief/general description of the study.The two letters included in this contact will be documented in the CPRS chart but included as a research related document that is not viewable to the Veteran.4) Study staff will attend staff meetings of participating mental health clinics to present the study.Flyers with study contact information will be provided so that anyone who is interested may contact the team directly.5) Study staff will conduct pre-screening of selected out-patient clinics within the VAPORHCS to identify potential participants, for example, Women Veterans Health Clinic.We have requested a partial HIPAA waiver for this purpose.The clinical providers of potentially eligible participants will be contacted to request that they inform the patient of the study.Additionally, study staff will send opt-out letters to these identified potential participants as a means of recruitment (see Appendix 2).6) Recruitment will also be done outside of the VA setting.Study staff will place flyers in clinics, centers, college campuses, and other locations in the community which have the potential to reach women Veterans.Study staff will get consent from these locations prior to posting the flyers.In addition, study staff will attend community events geared towards Veterans in order to explain the research study to providers and provide information to those who may be interested.Note: The study team will not be recruiting non-Veterans into the study but will expand recruitment efforts outside the VA setting.7) To supplement provider referrals in Portland, we may also conduct initial outreach to potentially eligible participants via recruitment letters, as required by the IRB.In addition to patients identified via pre-screening, we propose to use the VA Informatics and Computing Infrastructure (VINCI) databases to identify patients at the VA Portland Health Care System who may be eligible for participation in the research study.We will ask the VINCI data managers to pull requested data from the Corporate Data Warehouse (CDW).The data pulled from VINCI will include patient names, phone numbers and address, dates, social security number, visit and hospital information, and other health information.This information will be necessary to recruit participants, and a partial HIPAA authorization waiver will be requested.These identified data will be directly transferred electronically from the VINCI environment to the secured research server VHAATGFPC10 located in the OIT server room at the facility then to the secure research folder at VAPORHCS.This will be done by Christine Jasien, Atlanta VAMC statistician.The servers are managed by the respective OIT offices and security is managed by the Information Security Officers at that facility.The server room has appropriate security controls in place (including a locked room, password protection, and encryption), and the drive that the data will reside at will be controlled so that only the research team has access to the data.Patients identified for contact will be sent an IRB-approved letter referring to the study as "Project Stress-Less" for privacy purposes.The study team will discuss the study with interested patients by telephone, providing further information about the study.The PI will request a partial HIPAA waiver in order to conduct these prescreening/recruitment activities which facilitate identification of eligible participants.Recruitment rates will be calculated by comparing the total number of patients screened for the study to the number of patients who provide informed consent to participate.

Data Collection (See Table 1: Study Flowchart and Data Collection Schedule)
Participants will be assessed at five time-points during the study.Following the phone pre-screening interview, the participant will be scheduled for the Screening/Consent Visit (Time 0) for further determination of eligibility.If eligible, participants will be scheduled for the Baseline/Randomization Visit (Time 1) followed by the Mid-Treatment Visit (Time 2), the 2-Week Post Treatment Visit (Time 3) and the 3-Month Follow-Up Visit (Time 4).Each study visit will last 2-3 hours and includes collection of self-report measures, interview-based assessments, psychophysiological assessment, and immunological measures.Finally, if the participant completes intervention and elects to participate in the crossover intervention, they will be asked to complete several self-report measures (PCL, BDI, BPI, PSQI, VR-12 & Treatment Evaluation Form) before treatment, midway through treatment and again 2weeks and 3-months post treatment.Participants opting to do the crossover intervention will not be compensated and will be given the option to complete the measures via phone.

Self-Report and Interview-Based Assessments
Participant self-report and interview-based assessments will be administered on paper forms or via direct entry of fully de-identified data into the VA REDCap web-based application.Various self-report forms and interviews will be administered at each study visit.The following self-report and interview-based measures will be used for patient assessment during the course of the study:

Medical Outcomes
Adverse Events will be assessed at each time-point.Concomitant Medications will be assessed at the Baseline/Randomization Visit and any changes will be documented at follow-up visits.
VA Group Engagement will be assessed at all timepoints to determine if the Veteran is engaged in other groups and if so, which groups and how frequently they attend.

Demographics
A Basic Demographics form will be administered at the screening visit and updates to demographics and contact information will be assessed at each followup visit.
Currently enrolled participants that have consented to additional demographic survey questions, will be administered a sexual orientation and gender identify (SOGI) survey.New participants enrolled will be administered the SOGI survey during the demographics portion of the screening visit.

Trauma Exposure:
The Deployment Risk and Resilience Inventory-2 78 (DRRI-2) was prepared with support from the Department of Veterans Affairs and contains questions regarding experiences before, during and after deployment.For purposes of this study, Section D (Combat Experiences) will be administered to assess level of combat exposure.
The Childhood Trauma Questionnaire (CTQ) assesses exposure to and severity of childhood trauma across five subscales including: physical neglect, physical abuse, emotional neglect, emotional abuse and sexual abuse.The Life Events Checklist (DSM-5 version) is a self-report measure with established psychometrics designed to screen for potentially traumatic events in a respondent's lifetime and has been used with Veterans 79 .PTSD Severity: The Clinician Administered PTSD Scale (CAPS-5) is the gold-standard for assessing PTSD.The CAPS uses a clinician-administered diagnostic instrument that assesses lifetime and current PTSD diagnosis and symptoms and global PTSD symptom severity 80 .The CAPS also yields a continuous measure of the severity of both overall PTSD and of the four PTSD symptom clusters.It assesses the validity of the participant's responses and has excellent psychometric properties.The Past-Month version will be administered at Baseline and the Past Week version will be administered at each of the follow-up visits.CAPS-5 interviews will be audiorecorded for quality assurance purposes.
The PTSD Checklist (PCL-5) is a 20-item self-report rating-scale instrument that parallels diagnostic criteria for PTSD, as delineated in the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) 81 .The PCL is the standard measure of PTSD symptoms in the VA and can be used to determine PTSD diagnosis and PTSD symptom severity.

Psychiatric Symptoms/Diagnoses:
The MINI International Neuropsychiatric Interview-Version 82 (MINI) 7.0.0 will be administered to assess participant's mental health symptoms/diagnoses according to DSM-V criteria.MINI Interviews will be audio recorded for quality assurance purposes.
The Beck Depression Inventory-II (BDI-II) is a 21-item psychometrically sound selfreport rating scale of the common symptoms of depression and the severity of these symptoms 83 .The Difficulties in Emotion Regulation Scale (DERS) is a brief, 36-item, self-report questionnaire designed to assess multiple aspects of emotion dysregulation.The measure yields a total score as well as scores on six scales derived through factor analysis.
The Dissociative Experiences Scale (DES) is a 28-question self-report form developed as a screening tool for Dissociative Identity Disorder.

Symptoms:
The Brief Pain Inventory 84 is a widely used measurement tool for assessing pain severity and pain interference.The Pittsburgh Sleep Quality Index (PSQI) is a self-report scale consisting of 19 items that produce a global sleep quality score and the following seven component scores: sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, use of sleeping medications, and daytime dysfunction 85 .The PSQI has established internal consistency and reliability in various clinical populations of women (Cronbach alphas 0.80 across groups).The Berlin Questionnaire 86 for sleep obstructive apnea is a 10-item questionnaire well-known for its accuracy in predicting the presence of sleep apnea in patients.It has established sensitivity and specificity (Cronbach alphas 0.86 and 0.77, respectively, when polysomnography was used for confirmation).The Epworth Sleepiness Scale 87 is an 8-item self-report measure which provides a measure of a general level of daytime sleepiness, or average sleep propensity in daily life.It is widely used for making this assessment.The Patient Health Questionnaire-15 (PHQ-15) is a 15 item scale that inquires about somatic symptoms or symptom clusters that account for more than 90% of the physical complaints reported in the outpatient setting and include 14 of the 15 most prevalent DSM-V somatization disorder somatic symptoms 88 .It has demonstrated internal consistency and convergent validity with the BDI (r = 0.559; p < 0.01).

Social Functioning and Quality of Life:
The Veterans RAND 12 Item Health Survey 89 (VR-12) is a 12-item instrument used to measure health related quality of life and will be administered at various timepoints.
The PROMIS ® instruments use modern measurement theory to reliably and validly assess patient-reported outcomes (PROs) for clinical research and practice.The PROMIS ® short forms for social functioning will be used in the proposed study.

Sexual Orientation and Gender Identity (SOGI):
In the current study, we will expand data collection of demographic variables to include sexual orientation and gender identity based on current recommendations for inclusive research.Currently enrolled participants in the study will be asked to verbally consent to participate in a follow-up phone visit to complete a demographic survey lasting no more than 15 minutes.This follow-up survey will include pertinent demographic items including sexual orientation and gender identity.Research team members will review the electronic medical record of the enrolled participants to gather their most current phone number and address.Currently enrolled participants will then be contacted by phone.If the participants are unable to be reached by phone within 10 days of first contact, a letter will be sent to the last known address of the participant.This letter will provide information regarding the follow-up visit and how to complete the visit or opt-out of the visit.All future participants will complete the SOGI demographic survey as part of their initial visit and will not require an additional follow-up phone visit.

Dark Enhanced Startle Assessment (Atlanta Only)
Dark enhanced startle response will be assessed using a paradigm in which acoustic startle (blink) response is assessed in darkness versus light conditions.Data will be collected by trained research staff using Biopac MP150 for Windows.The acquired data will be processed using Mindware software and then exported to Excel for analyses.Dark enhanced startle data will be collected at Baseline, 2-Weeks Post and 3-Months Post Treatment.

Heart Rate Variability Assessment
In order to measure heart rate variability, we will utilize the Firstbeat Bodyguard-2 90 device which is a reliable R-R interval recording device for short and long-term measurements.The device is lightweight and user friendly.The device is attached directly to the skin with two chest electrodes and begins recording data

Table 1: Study Flowchart and Data Collection Schedule Study Intervention Trauma Center-Trauma Sensitive Yoga
The yoga intervention consists of a standardized trauma-sensitive Hatha yoga protocol developed by Emerson, Spinazzola and colleagues for use with civilian women with treatment-resistant PTSD 63 .Hatha yoga is a general term to describe the practice of physical postures, breath work, and mindfulness-what is commonly referred to in the West simply as "yoga."There are many styles of Hatha yoga (e.g., Iyengar, vinyasa, Ashtanga, Bikram), but when the term Hatha yoga is used in the West in contrast to another specified style, it most often designates a more gentle, slower-paced approach to the physical postures.Our protocol uses this gentler, slower approach.It involves ten weekly 90-minute group sessions of Trauma Center-Trauma Sensitive Yoga.Sessions address themes related to establishing safety, individual choice, being in the present moment, and taking effective action.The intervention will be conducted by yoga teachers certified in Trauma Center-Trauma Sensitive Yoga.Study staff will provide participants in the yoga intervention with detailed information related to the sessions.In addition, instructional DVDs will be provided to participants in the yoga intervention to facilitate practice at home.For participants who do not have access to a DVD player, a link will be provided which will direct participants to the private online videos on YouTube.These videos are hidden from the public, therefore the only way to gain access is by entering the link provided by the study team.Finally, reminder calls will be made each week to ensure optimal group attendance.During follow-up visits, study staff will assess whether participant engaged in at-home TC-TSY practice, and the frequency of at-home practice (via use of DVD/online videos, breathing techniques etc.) using an intervention tracking form.

Cognitive Processing Therapy-Cognitive
The control group, Cognitive Processing Therapy (CPT), is one of the gold-standard therapies for PTSD treatment in the VA mental health system.CPT is a cognitively-based, trauma focused treatment which will be led by two licensed clinical social workers who work in the Women's Trauma Program.As per the treatment protocol, there are twelve 90minute weekly sessions.The group sessions focus on identifying how thoughts change as a result of trauma exposure and ways in which to realistically evaluate these maladaptive thoughts and come up with more accurate alternative thoughts.Also per protocol, group members do not share their specific trauma details in group.These sessions will be conducted concurrently with the yoga intervention throughout the course of the study.Study staff will provide participants in the CPT group with detailed information related to the sessions.Reminder calls will be made each week to ensure optimal group attendance.During follow-up visits, study staff will assess the degree to which participant engaged in homework assignments and used strategies learned in group using an intervention tracking form.Compensation (Atlanta) Participant compensation will be provided following each study visit and following each treatment session.Participants will receive $40 for completion of the Screening/Consent, Baseline/Randomization and Midpoint Visits.For completion of the 2-Week and 3-Month post-treatment visits, participants will receive $60.For each treatment session, participants will receive $15. Compensation will be sent in the form of a VA check or via direct deposit.Each method of payment will be discussed and participants will indicate their preference at the initial visit.Eligible participants who consent and complete the substudy will receive $60 once they have completed the sleep study.The total possible compensation for completion of the study is $480.In certain cases, if the participant has to return a second time to complete a study visit, they may receive additional compensation of up to $20.For visits when the participant receives the heart-rate variability monitor, compensation will be sent as soon as the device is returned to the study site.Participants taking part in the crossover intervention will not receive compensation for completion of the study forms.

Compensation (Portland)
Participant compensation will be provided following each study visit and following each treatment session.Participants will receive $40 for completion of the Screening/Consent, $60 for Mid-treatment and 3-Month Follow-up visit, and $85 for the Enrollment/Baseline/Randomization and 2-Week Post-Treatment Visits.For each treatment session, participants will receive $10 for which they attend.Compensation will be sent in the form of a VA check or via direct deposit.Each method of payment will be discussed, and participants will indicate their preference at the initial visit.The total possible compensation for completion of the study is $430-450.In certain cases, if the participant has to return a second time to complete a study visit, they may receive additional compensation of up to $20.For visits when the participant receives the heartrate variability monitor, compensation will be sent as soon as the device is returned to the study site.Participants taking part in the crossover intervention will not receive any compensation.

D. POTENTIAL RISKS/DISCOMFORTS TO STUDY PARTICIPANTS AND MEASURES TO PREVENT OCCURRENCE Self-Report and Interview-Based Assessments
The assessments include questions about exposure to stressors and other topics that might produce transitory distress in some individuals.There is the potential for participants to experience embarrassment or other negative consequences if some of the experiences were disclosed, particularly if their identity was linked to interview data.We think that these risks are minimal given the protections in place to maintain confidentiality and the plans to respond to participants who experience distress.

Study Interventions Trauma Center-Trauma Sensitive Yoga:
There are physical risks in participating in the yoga intervention, as well as the potential for emotional distress during yoga sessions.The protocol has been designed specifically for women with PTSD.It is expected that some women will experience intense emotion during the yoga.The protocol has been designed to mitigate these risks and address physical and emotional distress if necessary.

Cognitive Processing Therapy-Cognitive:
There is a risk for transitory psychological distress in participating in the control condition, cognitive processing psychotherapy.This intervention is evidence-based and manualized and some psychological distress is expected.Clinicians providing this intervention are highly trained to respond to any such distress.

Venipuncture
The blood draw may cause mild discomfort, bruising, redness, or swelling.Study staff will discuss the process of having blood drawn with the participant to determine if there are any concerns or past difficulties with having blood drawn.Pertinent information will be relayed to female Veterans with PTSD.

F. DATA MONITORING AND ANALYSIS Data Management
As part of this protocol, we will collect data via chart review, self-report form, interviewbased assessment, blood collection, heart-rate variability device, ECG report, polysomnogram and dark-enhanced startle testing (Atlanta only).Data will either be collected at the AVAMC Clinical Studies Center or the Trauma Recovery Program or Portland VA or Vancouver, WA VA location of the VAPORHCS and then subsequently transported back to respective VAMC for storage.Any sensitive data including consent forms, session sign-in sheets etc. will be transported in a blue lock-bag as outlined in the approved VA Research Data Inventory (Privacy and Data Security Section).Data will be captured, stored and processed in the following ways: Chart Review Data will be extracted from the VA medical record including diagnoses, active medications, and reportable adverse events (if applicable).These data will be added to the VA REDCap database.
Self-Report and Interview Data: Self-report and interview data will be captured through pen and paper measures or through direct data entry into the VA REDCap (Research Electronic Data Capture) project database using a VA-approved tablet.REDCap 89 is a secure, web-based application designed to support data capture for research studies.REDCap for VA is installed and accessible only behind the VA firewall and data is backedup nightly and every 6 hours.In addition, VA REDCap provides data de-identification features and restricts access to PHI at the user-level.Deidentified self-report and interview data will be securely exported from VA REDCap to Excel or SPSS and then uploaded to the VA password-protected research drive for analysis as needed.Periodically, deidentified selfreport and interview data will be submitted to the study statistician for data analysis and review.
Additionally, demographic information, including identifiers (study ID), for each participant will be stored in the REDCap database that is password-protected and accessible only by approved members of the research team.The research suite is locked at all times with access granted only to authorized personnel.Data residing on VA desktop computers are routinely backed up on a secure, off-site server.Thus, all data are protected from loss and are stored devoid of all patient identifiers.Cytokine Data: In Atlanta, blood samples will be collected by trained study staff or CSC staff in the Atlanta VA Clinical Studies Center and labelled with date, study ID, and visit number only.Initial sample processing will take place in the CSC lab by trained staff before being sent to another lab within the VA for final analysis.Any sample remaining after initial analysis will be stored until the end of the study at which point remaining specimen will be destroyed.Deidentified cytokine data will be sent from the lab to the project manager.These data will be stored on the secure VA research server and the VA REDCap database until being sent to the Emory statistician for analysis.In Portland, blood samples will be collected by trained study staff in the VAPORHCS and labelled with date, study ID and visit number only.Initial sample processing will take place in the Loftis Lab at the VAPORHCS prior to shipment to the CSC of the AVAHCS for analysis.Any sample remaining after initial processing will be stored until the end of the study at which point remaining specimens will be destroyed.Heart Rate Variability (HRV) Data: At both sites, HRV data will be captured using the portable Bodyguard device which participants will wear for up to 48 hours.In Atlanta, once the device is returned to study staff, deidentified HRV data from the USB device will be downloaded to either an Emory laptop or VA computer that belongs to the PI and contains data analysis software.The data will then be analyzed by trained study staff and exported to Excel.Periodically, the data will be retrieved from the laptop and uploaded to Box.net.Dr. Amit Shah (Cardiologist/Co-Investigator) will assist the study staff with troubleshooting any issues and address any questions that arise during the data analysis process.Dr. Shah will process the de-identified HRV data on his Emory workstation for generation of heart rate variability metrics.Data, although de-identified, will be transferred via HIPAA compliant methods, including encrypted VA-issued USB differences between the groups (two-group independent t-tests effect size (Cohen's d) of 0.555 and chi-square tests for differences in proportions between the two-groups effect size (Cohen's omega, ω) 0.274 and higher) as well as moderate-to-large effect sizes detected for differences between the groups over time (repeated measures group-by-time interaction effects: effect size of 0.28, Cohen's f) will be detected.Power analyses will be completed using PASS v.13.0.8 91 .

Statistical Analysis
Comparisons between the groups at baseline will be run using t-tests, Mann Whitney nonparametric tests, and chi-square tests as appropriate.However, when numerical transformations are not sufficient, non-parametric and generalized non-normal response functions may also be employed.Multilevel mixed models (MLM) will be used instead of repeated-measures analysis of variance (RM-ANOVA), to analyze the differences between the groups over time.As opposed to RM-ANOVA which assumes independence between time points and assumes complete data for all subjects at all time-points, MLM adjusts for attrition (missing data) over time and applies appropriate correlation structure between the time points 92 .Multilevel modeling also provides insight into the variance components of the outcomes relative to those related to within-subject variability over time and those related to between-subject differences.These variance components are important for understanding the utility of each measure relative to reliably assessing each outcome.Generalized functions of these MLM models may also be run for non-normal outcomes due to highly skewed or zero-inflated data (common with biomarker and some behavioral measures) or binary outcomes (e.g.diagnosis determinations).These statistical modeling approaches will be applied appropriately to the outcome measures of interest for each of the three research aims.SPSS Version 22.0 will be used for all statistical analyses.

G. TRAINING
All study team members have completed the web-based Collaborative IRB Training Initiative (CITI) Program in the Protection of Human Subjects Research.The Project Manager will ensure that all study team members stay current with all required Emory and VA research trainings.
In addition, for all study team members working directly with participants, trainings will be conducted on the administration of structured interviews (CAPS, MINI), informed consent process, psychophysiological data collection, ECG, HRV data collection, phlebotomy (if applicable) and specimen processing.Once the staff member has met all training requirements for each item, they can begin working with study participants.
A detailed log of all study-related trainings will be maintained throughout the study.

H. DATA AND SAFETY MONITORING PLAN Data and Safety Monitoring Plan (DSMP)
Safety Monitoring: The PI or anyone else who has contact with study participants during study activities have the responsibility to monitor for any potential adverse events and protocol deviations.Any potential participant for an adverse event will be reported immediately via "warm transfers" per VA guidelines at respective site and PI, who will contact the participant and determine if additional intervention is needed to ensure participant safety.Study personnel will be trained on these procedures, including contacting VA Police, on-call Mental Health providers Veterans Crisis Line and/or local crisis lines, Protocol deviations will also be immediately reported to respective site PI who will ensure that adverse events deemed to be unanticipated problems and protocol deviations are properly reported to the IRB in a timely manner.Detailed written documentation will be kept for all adverse events that occur over the course of the study.PI will hold regular meetings with study staff where they will discuss adverse events and protocol deviations associated with this project and ways to reduce repeat occurrences.Research staff will examine all cumulative adverse events quarterly to determine if there are any systematic problems and to implement protocol corrections as needed after receiving IRB approval.Data Monitoring: All information linking study data to PHI will be kept within VHA electronically in secure computer files stored behind firewalls requiring password access, or in hardcopy form in locked file cabinets in locked offices.All patient identifiers will be removed prior to analysis.All investigators and team members who will have access to the data will have received appropriate background checks as part of hiring and/or credentialing and will have completed Data Security Training within the prior 12 months.Per VHA guidelines, data resulting from this study will be stored locally on VHA password-secure folders.Requests for data access will be considered and responded to within one month of the request and datasets will be made available electronically.
Requests must be made in writing to the study PI and provide information on the purpose for accessing the data.All data used in final, published results will be made available for sharing.Published data will be available upon request to any investigator in order to enable independent validation and interpretation of published data.
Once the current study is closed, we will store de-identified, anonymized dataset in an approved data repository consistent with policies in 1200.12 (Use of Data and Data Repositories in Research).A sharing agreement will prohibit the recipient from identifying or re-identifying (or taking steps to identify or re-identifying (or taking steps to identify or re-identify) any individual whose data are included in the dataset.

Adverse Event Reporting
The principal investigator will be responsible for following adverse event reporting requirements as outlined below in the protocol.These responsibilities include: 1) reviewing the accuracy and completeness of all adverse events reported, 2) compliance with local IRB policies for reporting adverse events and/or serious adverse events, and 3) overseeing monitoring of research volunteers at each follow-up visit and as indicated by notification by the yoga teachers at each yoga intervention session.Relatedness involves an assessment of the degree of causality between the study intervention and the event.The PI will perform an assessment of relatedness, in conjunction with Dr. Skelton, who has significant experience in data safety monitoring.All AEs with a reasonable, causal relationship to the intervention will be considered "related."A definite relationship does not need to be established.

AE and SAE Monitoring
For the proposed study, participants will be monitored at each data collection point and as indicated by notification from the yoga/CPT teachers at each intervention session.
Adverse events and serious adverse events will be assessed for relatedness to study participation and whether the event was anticipated or unanticipated.Those adverse events found to be unanticipated and related to study participation will be reported to IRB and VA R&D according to local reporting guidelines.

Safety Assessments
Safety assessments will be conducted with any study participant who reports new onset of: suicidal or homicidal thoughts, psychosis, substance use, or physical pain/symptom or physical injury that is determined to require medical evaluation beyond evaluation conducted within the TRP by Dr. Skelton or her designee.

Expedited Reporting of SAEs
Serious Adverse Events found to be related to participation in the research will be reported to IRB and Atlanta VA R&D according to local reporting requirements.

Collaborative Research
This protocol describes a multi-site study to be conducted at the AVAHCS and the VAPORHCS.AVAHCS is the coordinating center with VAPORHCS recently added as an additional site.As the primary site/coordinating center, study staff of the AVAHCS will be responsible for equivalent study procedures described in this protocol but conducted in Atlanta.Additionally, AVAHCS study staff will be responsible for assistance in screening for the purposes of recruitment and the storage and analysis of biophysiological data that is collected from participants of VAPORHCS.Where applicable, these tasks have been described as to be conducted at AVAHCS.Project Management of the coordinating center is being conducted by Terri Haywood (Terri.Haywood@va.gov;404-321-6111, ext.207026).

Certificate of Confidentiality
N/A.The study does not include a Certificate of Confidentiality Disclosure/Sharing N/A.The study does not include disclosure/sharing outside the IRB-approved VAPORHCS and AVAHC study personnel.